Innate Immunity Stimulation Via Toll-Like Receptor 9 Ameliorates Vascular Amyloid Pathology in Tg-SwDI Mice with Associated Cognitive Benefits

Overview

Journal J Neurosci

Specialty Neurology

Date 2017 Jan 27

PMID 28123027

Citations 41

Authors

Henrieta Scholtzova

Eileen Do

Shleshma Dhakal

Yanjie Sun

Shan Liu

Pankaj D Mehta

Thomas Wisniewski

Affiliations

Soon will be listed here.

Abstract

Significance Statement: Recent genetic studies have underscored the emerging role of microglia in Alzheimer's disease (AD) pathogenesis. Microglia lose their amyloid-β-clearing capabilities with age and as AD progresses. Therefore, the ability to modulate microglia profiles offers a promising therapeutic avenue for reducing AD pathology. Current immunotherapeutic approaches have been limited by poor clearance of a core AD lesion, cerebral amyloid angiopathy (CAA). The present study used Tg-SwDI mice, which have extensive CAA. We found that stimulation of the innate immune system and microglia/macrophage activation via Toll-like receptor 9 using CpG (cytosine-phosphate-guanine) oligodeoxynucleotides (ODNs) leads to cognitive improvements and CAA reduction, without associated toxicity. Our data indicate that this novel concept of immunomodulation represents a safer method to reduce all aspects of AD pathology and provide essential information for potential clinical use of CpG ODN.

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References

Doi Y, Mizuno T, Maki Y, Jin S, Mizoguchi H, Ikeyama M . Microglia activated with the toll-like receptor 9 ligand CpG attenuate oligomeric amyloid {beta} neurotoxicity in in vitro and in vivo models of Alzheimer's disease. Am J Pathol. 2009; 175(5):2121-32. PMC: 2774075. DOI: 10.2353/ajpath.2009.090418. View

Rego A, Viana S, Fontes Ribeiro C, Rodrigues-Santos P, Pereira F . Monophosphoryl Lipid-A: A Promising Tool for Alzheimer's Disease Toll. J Alzheimers Dis. 2016; 52(4):1189-202. DOI: 10.3233/JAD-151183. View

Boutajangout A, Li Y, Quartermain D, Sigurdsson E . Cognitive and sensorimotor tasks for assessing functional impairments in mouse models of Alzheimer's disease and related disorders. Methods Mol Biol. 2012; 849:529-40. PMC: 3859369. DOI: 10.1007/978-1-61779-551-0_35. View

Campbell J, Cho Y, Foster M, Kanzler H, Kachura M, Lum J . CpG-containing immunostimulatory DNA sequences elicit TNF-alpha-dependent toxicity in rodents but not in humans. J Clin Invest. 2009; 119(9):2564-76. PMC: 2735936. DOI: 10.1172/JCI38294. View

Feng Y, Li L, Sun X . Monocytes and Alzheimer's disease. Neurosci Bull. 2011; 27(2):115-22. PMC: 5560348. DOI: 10.1007/s12264-011-1205-3. View

Brothers H, Wilcock D . Are inflammatory profiles the key to personalized Alzheimer's treatment?. Neurodegener Dis Manag. 2015; 3(4):343-351. PMC: 4300199. DOI: 10.2217/nmt.13.40. View

Yamada M . Cerebral amyloid angiopathy: emerging concepts. J Stroke. 2015; 17(1):17-30. PMC: 4325636. DOI: 10.5853/jos.2015.17.1.17. View

Asuni A, Boutajangout A, Scholtzova H, Knudsen E, Li Y, Quartermain D . Vaccination of Alzheimer's model mice with Abeta derivative in alum adjuvant reduces Abeta burden without microhemorrhages. Eur J Neurosci. 2006; 24(9):2530-42. PMC: 1779823. DOI: 10.1111/j.1460-9568.2006.05149.x. View

Streit W, Xue Q, Tischer J, Bechmann I . Microglial pathology. Acta Neuropathol Commun. 2014; 2:142. PMC: 4180960. DOI: 10.1186/s40478-014-0142-6. View

10.

Chen G, Chen K, Knox J, Inglis J, Bernard A, Martin S . A learning deficit related to age and beta-amyloid plaques in a mouse model of Alzheimer's disease. Nature. 2001; 408(6815):975-9. DOI: 10.1038/35050103. View

11.

Wes P, Sayed F, Bard F, Gan L . Targeting microglia for the treatment of Alzheimer's Disease. Glia. 2016; 64(10):1710-32. DOI: 10.1002/glia.22988. View

12.

Iliev A, Stringaris A, Nau R, Neumann H . Neuronal injury mediated via stimulation of microglial toll-like receptor-9 (TLR9). FASEB J. 2003; 18(2):412-4. DOI: 10.1096/fj.03-0670fje. View

13.

Streit W, Braak H, Xue Q, Bechmann I . Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer's disease. Acta Neuropathol. 2009; 118(4):475-85. PMC: 2737117. DOI: 10.1007/s00401-009-0556-6. View

14.

Minett T, Classey J, Matthews F, Fahrenhold M, Taga M, Brayne C . Microglial immunophenotype in dementia with Alzheimer's pathology. J Neuroinflammation. 2016; 13(1):135. PMC: 4890505. DOI: 10.1186/s12974-016-0601-z. View

15.

Scholtzova H, Kascsak R, Bates K, Boutajangout A, Kerr D, Meeker H . Induction of toll-like receptor 9 signaling as a method for ameliorating Alzheimer's disease-related pathology. J Neurosci. 2009; 29(6):1846-54. PMC: 2699573. DOI: 10.1523/JNEUROSCI.5715-08.2009. View

16.

Kitazawa M, Cheng D, Tsukamoto M, Koike M, Wes P, Vasilevko V . Blocking IL-1 signaling rescues cognition, attenuates tau pathology, and restores neuronal β-catenin pathway function in an Alzheimer's disease model. J Immunol. 2011; 187(12):6539-49. PMC: 4072218. DOI: 10.4049/jimmunol.1100620. View

17.

Lai A, McLaurin J . Clearance of amyloid-β peptides by microglia and macrophages: the issue of what, when and where. Future Neurol. 2012; 7(2):165-176. PMC: 3380064. DOI: 10.2217/fnl.12.6. View

18.

Prokop S, Miller K, Drost N, Handrick S, Mathur V, Luo J . Impact of peripheral myeloid cells on amyloid-β pathology in Alzheimer's disease-like mice. J Exp Med. 2015; 212(11):1811-8. PMC: 4612091. DOI: 10.1084/jem.20150479. View

19.

Andreasson K, Bachstetter A, Colonna M, Ginhoux F, Holmes C, Lamb B . Targeting innate immunity for neurodegenerative disorders of the central nervous system. J Neurochem. 2016; 138(5):653-93. PMC: 5433264. DOI: 10.1111/jnc.13667. View

20.

Karch C, Cruchaga C, Goate A . Alzheimer's disease genetics: from the bench to the clinic. Neuron. 2014; 83(1):11-26. PMC: 4120741. DOI: 10.1016/j.neuron.2014.05.041. View